The liking of sweetness probably evolved to maximize the evolutionary fitness of humans, but it now detracts from our physical fitness, increasing the prevalence of obesity (which is due in part to the overconsumption of sweet, calorie-rich foods) and exacerbating the symptoms of diabetes. Other animal species also like sweet foods and drinks, and therefore we propose a comparative approach to study the preference for sweetness and taste receptors (T1R family) using closely related animal species that differ markedly in their behavior toward sweet taste. Specifically, we will study members of the Order Carnivora because they provide a wide range of sweet taste behavior and because preliminary results suggest a mechanism for these species differences: cats do not like sugar and also have a microdeletion in one subunit of the sweet receptor gene that renders it nonfunctional. Additional preliminary data suggest that other Carnivora species that have a functional sweet receptor also have a preference for sugars but do not show preferences for high-intensity sweeteners (with some interesting exceptions). In the research we propose here, we will test the hypothesis that the structure and function of sweet taste receptors in Carnivora species affect species-specific taste preferences, and that these in turn are reflected in species food choices. In Aim 1 we will sequence the genes for all three members of the T1R taste receptor family, Tas1r1, Tas1r2, and Tas1r3, from 15 Carnivora species (meerkat, domestic cat, ferret, genet, lesser and giant panda, South American coati, walrus, Pacific Harbor seal, sea lion, spotted hyena, red wolf, striped skunk, fossa, and banded linsang). In Aim 2 we will perform behavioral studies of these same species to evaluate their behavioral responses to 12 sweet stimuli: six natural sugars and six high-intensity sweeteners In Aim 3, we will functionally express the receptor genes of these Carnivora species in a cell- based assay system (based on data obtained in Aim 1 and 2). The patterns of differences among these species will help us identify the structural features of taste receptors that underlie their binding specificity for sugars, high-intensity sweeteners, and potentially other compounds. Results of this research will provide new insights into the nature and function of taste receptor genes and how their variation affects taste perception, thereby adding to our understanding of the molecular basis of the human sweet tooth. PUBLIC HEALTH RELEVANCE: Like many genes, those coding for the sweet receptor are highly conserved among mammals, but the sites where animals differ in amino acid sequence are related to their unique taste preferences and habitual diets. By examining the variations in DNA sequence among diverse species of Carnivora, some of which are indifferent to sweet and some of which are avid sweet- likers, the structure of the receptor and its function can be better understood, leading to interventions to palliate the human overconsumption of sweet carbohydrates.